Jitendra Mishra
Scripps Research Institute
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Jitendra Mishra.
Cancer Research | 2014
Joanne R. Doherty; Chunying Yang; Kristen E.N. Scott; Michael D. Cameron; Mohammad Fallahi; Weimin Li; Mark A. Hall; Antonio L. Amelio; Jitendra Mishra; Fangzheng Li; Mariola Tortosa; Heide Marika Genau; Robert J. Rounbehler; Yunqi Lu; Chi V. Dang; K. Ganesh Kumar; Andrew A. Butler; Thomas D. Bannister; Andrea T. Hooper; Keziban Unsal-Kacmaz; William R. Roush; John L. Cleveland
Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH). Reductions in GSH then lead to increases in hydrogen peroxide, mitochondrial damage, and ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.
Bioorganic & Medicinal Chemistry | 2013
David Richard; Ryan Lena; Thomas D. Bannister; Noel Blake; William E. Pierceall; Nicole Carlson; Christina Eberhart Keller; Marcel Koenig; Yuanjun He; Dmitriy Minond; Jitendra Mishra; Michael D. Cameron; Timothy P. Spicer; Peter Hodder; Michael H. Cardone
Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic.
Journal of Biomolecular Screening | 2010
Franck Madoux; Scott Simanski; Peter Chase; Jitendra Mishra; William R. Roush; Nagi G. Ayad; Peter Hodder
The tyrosine kinase Wee1 is part of a key cellular sensing mechanism that signals completion of DNA replication, ensuring proper timing of entry into mitosis. Wee1 acts as an inhibitor of mitotic entry by phosphorylating cyclin-dependent kinase CDK1. Wee1 activity is mainly regulated at the protein level through its phosphorylation and subsequent degradation by the ubiquitin proteasome pathway. To facilitate identification of small molecules preventing Wee1 degradation, a homogeneous cell-based assay was developed using HeLa cells transiently transfected with a Wee1-luciferase fusion protein. To ensure ultra-high-throughput screening (uHTS) compatibility, the assay was scaled to a 1536-well plate format and cells were transfected in bulk and cryopreserved. This miniaturized homogeneous assay demonstrated robust performance, with a calculated Z′ factor of 0.65 ± 0.05. The assay was screened against a publicly available library of ~218,000 compounds to identify Wee1 stabilizers. Nonselective, cytotoxic, and promiscuous compounds were rapidly triaged through the use of a similarly formatted counterscreen that measured stabilization of an N-cyclin B-luciferase fusion protein, as well as execution of viability assessment in the parental HeLa cell line. This screening campaign led to the discovery of 4 unrelated cell-permeable small molecules that showed selective Wee1-luciferase stabilization with micromolar potency. One of these compounds, SID4243143 (ML 118), was shown to inhibit cell cycle progression, underscoring the importance of Wee1 degradation to the cell cycle. Results suggest that this uHTS approach is suitable for identifying selective chemical probes that prevent Wee1 degradation and generally applicable to discovering inhibitors of the ubiquitin proteasome pathway.
Journal of Thermoplastic Composite Materials | 2000
S. Ray Chowdhury; Jitendra Mishra; Chirantan Das
The heat shrinkability of polymers, which depends on their elastic memory, is being utilized in various applications, mainly in the field of encapsulation. The elastic memory can be introduced into the system by the addition of an elastomeric phase. From the technological point of view, low-density polyethylene (LDPE) is an important polymer. Polyurethane shows excellent properties in terms of solvent resistance, oil resistance, and abrasion resistance. Here the blends of low-density polyethylene (LDPE) and polyurethane (PU) were studied with reference to their shrinkability introducing crosslinking in both phases. Various microstructural parameters have been examined to determine their effect on shrinkability. Shrinkability decreases with increase in elastomer content and with increase in cure time in the case of blends of fixed ratio, for all blends. Generally, the crystallinity of a high-temperature (H-T) stretched sample is higher than that of low-temperature stretched samples, which is again higher than that of the original sample. From the continuous cure characteristics studied by Monsanto Rheometer, torque was found to increase with increase in elastomer content. From high-temperature DSC it is found that with increase in PU content stability increases, and further high temperature processing decreases the initial degradation temperature but enhances the rate of degradation.
MedChemComm | 2016
R Nair; Jitendra Mishra; Fangzheng Li; Mariola Tortosa; Chunying Yang; Joanne R. Doherty; Michael D. Cameron; John L. Cleveland; William R. Roush; Thomas D. Bannister
Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells. Amino acid conjugation also improves the pharmacodynamic properties of experimental MCT1/2 inhibitors.
Cell Cycle | 2015
Clara Penas; Jitendra Mishra; Spencer D. Wood; Stephan C. Schürer; William R. Roush; Nagi G. Ayad
Ubiquitin mediated proteolysis is required for transition from one cell cycle phase to another. For instance, the mitosis inhibitor Wee1 is targeted for degradation during S phase and G2 to allow mitotic entry. Wee1 is an essential tyrosine kinase required for the G2/M transition and S-phase progression. Although several studies have concentrated on Wee1 regulation during mitosis, few have elucidated its degradation during interphase. Our prior studies have demonstrated that Wee1 is degraded via CK1δ dependent phosphorylation during the S and G2/M phases of the cell cycle. Here we demonstrate that GSK3β may work in concert with CK1δ to induce Wee1 destruction during interphase. We generated small molecules that specifically stabilized Wee1. We profiled these compounds against 296 kinases and found that they inhibit GSK3α and GSK3β, suggesting that Wee1 may be targeted for proteolysis by GSK3. Consistent with this notion, known GSK3 inhibitors stabilized Wee1 and GSK3β depletion reduced Wee1 turnover. Given Wee1s central role in cell cycle progression, we predicted that GSK3 inhibitors should limit cell proliferation. Indeed, we demonstrate that GSK3 inhibitors potently inhibited proliferation of the most abundant cell in the mammalian brain, the cerebellar granule cell progenitor (GCP). These studies identify a previously unappreciated role for GSK3β mediated regulation of Wee1 during the cell cycle and in neurogenesis. Furthermore, they suggest that pharmacological inhibition of Wee1 may be therapeutically attractive in some cancers where GSK-3β or Wee1 are dysregulated.
Archive | 2010
Yangbo Feng; Yen Ting Chen; Hampton Sessions; Jitendra Mishra; Sarwat Chowdhury; Yan Yin; Philip V. LoGrasso; Jun-Li Luo; Thomas D. Bannister; Thomas Schroeter
Archive | 2013
Thomas D. Bannister; Marcel Koenig; Yuanjun He; Jitendra Mishra; Timothy P. Spicer; Dmitriy Minond; Adrian Saldanha; Becky A. Mercer; Michael D. Cameron; Ryan Lena; Nicole Carlson; David Richard; Michael H. Cardone; Peter Hodder
Archive | 2011
Franck Madoux; Jitendra Mishra; Becky A. Mercer; Nagi G. Ayad; William R. Roush; Peter Hodder; Hugh Rosen
Archive | 2016
Thomas D. Bannister; William R. Roush; Jun Yong Choi; R Nair; Andy S. Tsai; Jitendra Mishra; John L. Cleveland